Despite the high concentration of docosahexaenoic acid in the retina, the function and dynamics of this molecule have not been established. We intend to investigate the dynamics of docosahexaenoic acid in the retina and in photoreceptor membranes under normal conditions and during the development of retinal degenerative diseases. The composition and metabolism of docosahexaenoate-containing phospholipids will be studied by a combination of biochemical and autoradiographic procedures in retinas from rats, mice and frogs. In addition, human retinas with retinitis pigmentosa obtained from eye bank eyes will also be analyzed. Two animal models of retinal degenerative disease will be compared and studied from the point of view of docosahexaenoate and phospholipid synthesis: one model demonstrates alterations in the pigment epithelium; the other shows changes in the photoreceptor membranes. The synthesis and acylation of docosahexaenoic acid will be followed during postnatal retinal development by in vivo injection f labeled precursors of fatty acids. The relationship of de novo biosynthesis and turnover of the polar head of phospholipids to docosahexaenoate metabolism will be surveyed in photoreceptor membranes and in neural retina. The effect of light and of depolarization on the metabolism of docosahexaenoate will be studied in photoreceptor membranes and synaptosomes. We will test the hypothesis that a significant proportion of th docosahexaenoate present in retinal lipids is introduced during the de novo biosynthesis of phosphatidic acid, from which it is diverted to other phospholipids. This may be an important pathway for the accumulation and retention of docosahexaenoate in the photoreceptor membranes after deacylation. Moreover, the formation of prostaglandins from free docosahexaenoic acid in photoreceptor membranes will be investigated. Amphiphilic cationic drugs will be used to redirect the phospholipid pathway and promote accumulation of acidic phospholipids enriched in docosahexaenoate. In addition, dietary manipulation of essential fatty acid sources will be employed to determine how the synthesis of docosahexaenoate-containing phospholipids is regulated. Such information may lead to improvements in the management of degenerative retinal diseases, especially if the degeneration can be halted or retarded by shifting membrane phospholipid metabolism with the use of drugs.